The candidate's immediate goal is to acquire critical scientific and clinical training to enable her to pursue independent investigation with the long-term goal of improving the outcome for recipients of hematopoietic cell transplantation (HCT) with umbilical cord blood (UCB). UCB is used as an alternative source of stem cells for HCT only when the patient cannot identify an otherwise suitable related or unrelated donor. This is secondary to poor outcomes following umbilical cord blood transplantation (UCBT), especially in adults and larger children, due to inadequate cell numbers in the graft leading to delayed engraftment that is often associated with lethal infection. The proposed grant will integrate two complimentary approaches: 1. the preclinical development of a novel ex vivo stem cell expansion system using Delta1, a Notch ligand that is a known regulator of cell fate determination, and 2. the clinical evaluation of outcomes of UCBT using ex vivo expanded cells. In preclinical studies, we hypothesize that UCB progenitor cells cultured on Notch ligand will result in self-renewal of repopulating cells, thereby increasing the number of these cells available for transplantation. Our laboratory has developed a novel expansion method for enhancing the repopulating capacity of hematopoietic progenitor cells, and in preliminary studies with cord blood progenitor cells, culture with engineered Notch ligand increased the number of CD34+ precursors and substantially enhanced their repopulating ability in immunodeficient mice. We further hypothesize that the effectiveness of this approach will depend on a number of critical variables, including dose of Notch ligand and signaling, choice of cytokines, starting cell population (CD34+ vs CD34+38-) and cell density. In clinical studies, the candidate will assess the outcome of UCBT using cells expanded by the above optimized methodology. Additionally, a rigorous didactic and mentoring program in clinical trial design will provide the candidate the foundation to implement and supervise clinical trials of conventional UCBT augmented with ex vivo expanded cells.